DESCRIPTION (Applicant's Description): Melanoma is a common and potentially devastating disease. In the United States, 42,000 new cases and 7,300 deaths due to melanoma occurred in 1998. Histopathological criteria are the primary factors used to predict prognosis; however, for intermediate to thick tumors (>1.5 mm), the ability to accurately predict prognosis is poor. Early metastases characteristic of melanoma are an ominous sign, as current therapies have little effect on survival. The lack of accurate prognostic i n d icators and effective therapies emphasize the need for a better understanding of the genetic and phenotypic changes in melanoma formation and progression. The 9p21 locus containing the overlapping ink4a and arf genes is frequently mutated or deleted in familial and sporadic melanomas and acts as a tumor suppressor. 10q24, which contains the pten locus, is thought to be the site of a second melanoma tumor suppressor. A mouse model for melanoma has recently been developed in which mice deficient in ink4a/arf express an activated from of RAS in melanocytes. These mice form nodular melanomas that do not metastasize. My goal is to evaluate the role of the PTEN pathway in melanoma formation and progression using this mouse melanoma model as a starting point. First, the subcellular localization of the forkhead related (FKHR) transcription factors will be used to determine the status of PTEN pathway signaling in RAS/INK4a melanomas, as activation of PTEN pathway signaling results in a change from nuclear to cytoplasmic FKHR localization. In addition, RAS/INK4a melanomas will be evaluated for pten deletions and mutations. Second, the effect of pten loss on normal melanocyte biology and on melanoma formation and progression in RAS/INK4a mice will be examined by melanocyte-specific pten knockouts. Lastly, the model will be refined for analysis of the genetic and phenotypic changes of metastasis. The applicant is an M.D. who will have completed a residency in anatomic pathology and a fellowship in dermatopathology prior to the proposed start date. He has also completed Ph.D. training in cell biology. The proposed research will be carried out in the laboratory of Dr. Ronald DePinho at the Dana-Farber Cancer Institute, an affiliate of the Harvard Medical School.